Cancer is thought to occur as a result of an immune system that is not properly removing uncontrolled proliferating cancer cells. Stimulating the immune system to recognize and eliminate cancerous cells has become a promising strategy for therapeutic treatments. Proleukin® (aldesleukin) contains a recombinant human Interleukin 2 (IL-2) thought to boost the immune system against cancer cells and is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC). Severe adverse events generally accompany this therapy at the recommended dosages. Thus, there is a need to identify improved methods.
The cytokine granulocyte macrophage colony stimulating factor (GM-CSF) enhances the adaptive immune system by enhancing antigen presentation and co-stimulation by dendritic cells (DC). Due to its immune stimulatory functions, GM-CSF has been used to augment host immune systems against cancer and to boost the white blood cell count for patients after chemotherapy. Provenge™ is a FDA-approved autologous cellular cancer immunotherapy treatment. Peripheral blood leukocytes of a subject are harvested via leukapheresis. These enriched monocytes are incubated with prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage colony stimulating factor (PAP-GM-CSF). GM-CSF is thought to direct the target antigen to receptors on DC precursors, which then present PAP on their cell surface in a context sufficient to activate T cells for the cells that express PAP. Activated, PAP presenting DCs are administered to the subject to elicit an immune response retarding cancer growth. This strategy requires isolation and expansion of cells of the subject, and typically treatment does not entirely clear the subject of cancer or tumors. Thus, there is a need to identify improved methods.
Interleukin 4 (IL-4) is a γ-chain cytokine. It serves as a signal to activate and elicit antibody class switching by B lymphocytes and converts naïve helper T lymphocytes to active T lymphocytes and then expand their population. U.S. Pat. No. 6,838,081 reports enhancing the development of antigen presenting cells from precursor cells by administering a combination of IL-4 and GM-CSF. See also U.S. Patent Application 2004/0072299 and Hikino et al., ANTICANCER RESEARCH 24: 1609-1616 (2004).
GIFT fusokines are the fused proteins derived from GM-CSF and common γ chain interleukin fusion transgenes and may either suppress or enhance host immune response. Stagg et al., Molecular Therapy, 2004, 9, S133-S133, disclose a GM-CSF/IL-2 Fusion (GIFT2). See also Penafuete et al., Cancer Res. 2009, 69(23):9020-8; Rafei et al., Nat Med. 2009, 15(9):1038-45; Williams and Park, Cancer, 1991, 67(10 Suppl):2705-7; WO 2005/0053579; WO 2005/026820; WO 2008/0014612; and U.S. Pat. Nos. 7,323,549; 7,217,421; 6,617,135; and 5,108,910.